Abstract
Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.
Highlights
Multiple myeloma (MM) is characterized by abnormally proliferating plasma cells derived from B cells [1] and ranks second as the cause of death from hematological malignancy [2]
We investigated the antimyeloma effects of histone deacetylase 6 (HDAC6)-selective inhibitors, A452 [33] and ACY-1215, in both BTZ-sensitive and BTZ-resistant MM cells
These results suggest that the HDAC6-selective inhibitor restores the sensitivity to BTZ by inactivating cell survival signaling in BTZ-resistant U266 cells
Summary
Multiple myeloma (MM) is characterized by abnormally proliferating plasma cells derived from B cells [1] and ranks second as the cause of death from hematological malignancy [2]. Typical symptoms of MM include anemia, bone destruction, hypercalcemia, infection, and renal failure due to impaired immune function [3]. The survival rate of MM patients has improved due to the development of autologous stem cell transplantation and novel therapeutic agents that include proteasome inhibitors (PIs) and immunomodulatory drugs [4]. Despite recent advances in MM treatment, most patients fall into cyclic relapse and eventually develop refractory disease due to residual MM [5]. Many researchers have reported the recurrence and drug resistance in MM patients who have previously received chemotherapy, which remains a major obstacle for curing MM. Because there are currently no effective therapies to treat chemotherapy-resistant
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